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J Allergy Clin Immunol. 2019 Jan 17. pii: S0091-6749(19)30034-X. doi: 10.1016/j.jaci.2018.12.1010. [Epub ahead of print]

Hematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT/ESID-IEWP-SCETIDE-PIDTC Study.

Author information

1
Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina, 58, 20132, Milan, Italy. Electronic address: ferrua.francesca@hsr.it.
2
Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano - Bicocca, via Cadore 48, Monza, 20900, Italy.
3
Paris Descartes-Sorbonne Paris Cité University, Institute Imagine, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
4
Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK; Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne - UK, NE2 4HH.
5
Department of Pediatric Immunology, Great Ormond Street Hospital, Great Ormond Street, WC1N 3JH, London, UK.
6
Paris Descartes-Sorbonne Paris Cité University, Institute Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris (APHP), 149 rue de Sèvres, F-75015 Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
7
Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology‬‬‬‬‬‬‬‬‬‬‬. 1 Samori Mashela str, ‬‬‬‬‬‬‬‬‬‬Moscow, Russia.
8
Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy.
9
Department of Pediatrics, King Faisal Specialist Hospital & Research Center, P.O. Box 3354, MBC 58, Riyadh 11211, Saudi Arabia.
10
Department of Pediatrics, King Faisal Specialist Hospital & Research Center, P.O. Box 3354, MBC 58, Riyadh 11211, Saudi Arabia; Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, 105 Grabiszynska Str. Wrocław, Poland.
11
Department of Pediatric Hematology and Oncology, University Hospital Motol Prague, V Uvalu 84, Prague 5, 150 06, Czech Republic.
12
Institut d'Hematologie et d'Oncologie Pediatrique, Hospices Civils de Lyon, 1 Place Joseph Renaut, 69008, Lyon, France.
13
L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12,Weigel Str. Wrocław, Poland; Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, 105 Grabiszynska Str. Wrocław, Poland.
14
Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
15
Immunology Department, Children's Memorial Health Institute, Av. Dzieci Polskich 20, 04-730 Warsaw, Poland.
16
Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, 5323 Harry Hines Boulevard, MC 9063, Dallas, TX 75390-9063, United States of America.
17
Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California San Francisco, 550 16th Street, 4th Floor, Box 0434, San Francisco, CA 94143, United States of America.
18
Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden.
19
Pediatric Oncology and Hematology Unit, Children Hospital, University Hospital Nancy, Rue du Morvan, 54500 - Vandoeuvre-les-Nancy, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
20
Pediatric Clinic, Rigshospitalet, Copenhagen, Denmark.
21
Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, D-89075, Ulm, Germany.
22
University Hospital Center Zagreb, Department of Pediatrics, Division of Allergology, Clinical Immunology, Respiratory Diseases and Rheumatology, Kispaticeva 12, 10000 Zagreb, Croatia.
23
Department of Pediatrics/Willem-Alexander Children's hospital, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
24
University Medical Centre Utrecht, Utrecht University, Department of Pediatrics, Lundlaan 6, 3584EA, Utrecht, The Netherlands; Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CX, Utrecht, The Netherlands.
25
Hématologie Adulte, Hôpital Necker, AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
26
Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, ARC 1216, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA.
27
Pediatric Hematology/Oncology, Dr. von Hauner University Children's Hospital, Munich, Germany.
28
Department of Pediatric Hematology and Oncology, Wroclaw Medical University, Borowska St. 213, Wroclaw, Poland.
29
Service d'hématologie pédiatrique, Hôpital de la Timone Enfants 264 Rue St Pierre, 13885 Marseille, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
30
Pediatric Stem Cell Transplantation, Columbia University College of Physicians and Surgeons, 3959 Broadway, CHN-1007, New York, NY 10032, USA.
31
Pediatric Hematology - Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.
32
University Children's Hospital of Cracow, 265 Wielicka St., 30-663 Cracow, Poland.
33
Pediatric Hematology and Oncology Department, Hospital Universitario MaternoInfantil Vall d'Hebron, Barcelona, Spain.
34
Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, 06100 Ankara, Turkey.
35
Department of Clinical Immunology and Transplantology, Jagiellonian University, Medical Collage, Transplantation Center University Children's Hospital in Krakow, Krakow, Poland.
36
Ankara University Medical School, Department of Pediatric Immunology-Allergy and BMT Unit, Mamak cad. Dikimevi, 06100 Ankara, Turkey.
37
United St. István and St László Hospital, Dept. of Pediatric Hematology and Stem Cell Transplantation; 1097 Budapest, Albert Flórián u. 5-7. Hungary.
38
Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
39
Department of Pediatrics, University Hospitals Leuven, Division of Pediatric Immunology, Department of Immunology and Microbiology, Catholic University Leuven, Leuven, Belgium.
40
Nationwide Children's Hospital, 700 Children's Drive - ED6023, Columbus, OH 43205 USA.
41
Pediatric Blood and Marrow Transplant, University of Minnesota, 420 Delaware Street SE‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬, MMC 484, Minneapolis, MN 55455‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬.
42
Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
43
Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Pediatric Blood Disorders, Immunodeficiency and SCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital.
44
Cancer Centre for Children, The Children's Hospital at Westmead, Hawkesbury Road, Sydney NSW 2145, Australia.
45
Cancer Centre for Children, The Children's Hospital at Westmead, Hawkesbury Road, Sydney NSW 2145, Australia; University of Sydney Medical Program, Australia.
46
University Medical Centre Utrecht, Utrecht University, Department of Pediatrics, Lundlaan 6, 3584EA, Utrecht, The Netherlands; Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CX, Utrecht, The Netherlands; Memorial Sloan Kettering Cancer Center: Dept. Pediatrics, BMT and Cell Therapies program, New York, USA; Laboratory for Translational Immunology, Tumor-immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
47
Department of BMT, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
48
Paris Descartes-Sorbonne Paris Cité University, Institute Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris (APHP), 149 rue de Sèvres, F-75015 Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France.
49
Center for Pediatrics and Center for Chronic Immunodeficiency, Medical Center - University Freiburg, Mathildenstrasse 1, 79106 - Freiburg, Germany.
50
Paris Descartes-Sorbonne Paris Cité University, Institute Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris (APHP), 149 rue de Sèvres, F-75015 Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; College de France, Paris, France.

Abstract

BACKGROUND:

CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).

OBJECTIVE:

We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.

METHODS:

We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables relevance with respect to survival and cure.

RESULTS:

Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 78.2%, 58.1% and 72.3% 5 years post-HSCT. Results were better in transplants performed ≥2000 and in children <10 years old at HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT ≤2 years from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC) and bone marrow-derived stem cells. Most rejections occurred after reduced intensity or non-myeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was ≥50% donor in 85.2%.

CONCLUSION:

HSCT is curative in CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS and DFS. Prospective studies are required to compare risks of HSCT with those of life-long supportive therapy.

KEYWORDS:

CD40 ligand; X-linked hyper-IgM syndrome; hematopoietic stem cell transplantation; primary immunodeficiency

PMID:
30660643
DOI:
10.1016/j.jaci.2018.12.1010
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